The invention relates to new artificial tissues, methods for the production and the use thereof, and to cell interaction systems for inducing artificial tissues for the purpose of producing vital transplants and establishing models of diseases. Such cell interaction culture systems for in vitro organ and tissue models are suitable for producing three-dimensional cell tissues using three-dimensional supporting structures which permit formation of an extracellular matrix (ECM) but initially, do not have any ECM themselves. The close interaction of artificial tissues permits setting up models of diseases where cell and matrix changes by external effects, e.g., by administration of medicaments, can be tested in boundary zones.
Numerous cell culture systems are known, wherein an extracellular matrix (ECM) has been described. Thus, the patent specification DE 3,410,631 presents an implantation material for repairing defective cartilage and bones, which either is in the form of a gel or embedded in natural or artificial bone material. The gel includes embryonic species-specific chondrocytes or mesenchyme cells and preferably also an extracellular matrix of chondrocytes and growth hormones. U.S. Pat. No. 4,801,299 (U.S. patent specification) suggests body implants in the form of an extracellular matrix based on collagen.
U.S. Pat. No. 4,935,000 is directed to a method for tissue regeneration using extracellular matrix induction. In addition, extracellular matrices are also used in context with human skin regeneration, cosmetic compositions (U.S. Pat. No. 5,055,298) and, on collagen or fibronectin basis, for attaching T-cells (U.S. Pat. Nos. 5,188,959 and 5,354,686). DE 4,336,399 describes collagen (type 1) as base matrix for the stationary phase of bipolar-adhered cell culture hepatocytes.
The DE 4,323,487 is directed to the functional immobilization of enzymes, proteins and whole cells on solid, biocompatible support materials by means of electrostatic interaction between the surface coating of the solid and the adsorbate to be fixed. WO 92/20780 (DE 4,116,7Z7) describes the simultaneous cultivation of various mammalian cells, the separate production of various mammalian cell products and the modeling of organ interactions on a humoral level.
In the production of implants, methods have become familiar starting from bundles of polymeric fiber made of an absorbable material, onto which the isolated and grown cells are applied and the bundles are implanted. WO 90/12603 reports three-dimensional supporting structures formed in the shape of the organ to be replaced and added with the desired cells. In three-dimensional supporting structures, however, there is the problem of providing sufficient nutrients for the cells in the interior of the implant.
DE 4,306,661 claims the production of implants from cell cultures. Therein, cartilage cells are applied onto an absorbable, pre-formed, three-dimensional supporting structure corresponding to the desired structure of the implant, and the structure is enveloped with a material allowing a nutrient solution to diffuse therethrough. In this way, an intercellular matrix may be formed by mutual binding of cells. During and after a transplantation, the artificially produced cartilage tissue is exposed to a number of negative effects jeopardizing long-term stability of the tissue (Buja J. et al., Ann. Rheum. Dis. April 1994, 53(4), 229-34). For example, this is particularly important in patients suffering from arthrosis or rheumatoid arthritis. Here, the implanted tissue must have a local effect against pathologically degenerative and inflammatory processes.
Several methods for producing transplantable cartilage-replacing tissue are known (Vacanti C. A. et al., Plastic and Reconstructive Surgery, 8, 753-759, 1991; Sittinger M. et al., Biomaterials 1994, 15, 451-456).
Also, ways have been described to provide cells of the joint interior skin with predominantly anti-inflammatory genes ex vivo and to re-implant them (Evans C. H. and P. D. Robbins, 1994: Gene Therapy for Arthritis, in Gene Therapeutics: Methods and Applications of Direct Gene Transfer; J. A. Wolff, editor, Birkhauser, Boston, 312-343).